Trehalose is a C2-symmetric disaccharide consisting of two glucose molecules linked together by a 1,1-α,α-glycosidic bond. Although trehalose is not present in mammals, it is widespread elsewhere in nature, where it primarily functions as an energy source and as a protectant against desiccation, osmotic stress, and changes in temperature. Trehalose metabolism is required for virulence in a number of pathogenic organisms, most notably Mycobacterium tuberculosis (Mtb), which is the causative agent of human tuberculosis (TB). Mtb is characterized by its complex cell envelope, which harbors a variety of trehalose glycolipids that are involved in cell-wall biosynthesis and that contribute to pathogenesis. The essentiality of trehalose metabolism in Mtb—coupled with its absence in humans—makes it an attractive target for drug and diagnostic development, a notion that is underscored by the recent identification of numerous antimycobacterial compounds that inhibit trehalose glycolipid transport.
Despite their potential value, the development and application of trehalose analogues in TB research remains limited, in large part due to the difficulties associated with their chemical synthesis. Specifically, the C2-symmetry and 1,1-α,α-glycosidic bond of trehalose pose significant challenges. Methods for the desymmetrization and regioselective hydroxyl group manipulation of trehalose are usually lengthy and low-yielding. On the other hand, methods for the formation of 1,1-α,α-glycosidic linkages are either laborious or suffer from low stereoselectivity. In addition to these technical obstacles, multi-step chemical synthesis of carbohydrates is often inefficient and inaccessible to non-experts.
A chemoenzymatic method for the synthesis of trehalose analogues would complement chemical methods and help to alleviate many of these problems. In general, enzymes can perform reactions with excellent regio- and stereoselectivity under mild conditions, and without the need for protection of substrate functional groups. Moreover, enzymatic reactions are easy to carry out, non-hazardous, and environmentally benign, making chemoenzymatic synthesis a cornerstone of “green” chemistry development. These attributes, coupled with the increasing focus on trehalose and its derivatives in various scientific fields, motivated us to develop a robust chemoenzymatic approach to trehalose analogue synthesis.